Hypolipidemic and antiatherosclerotic 4-(polyfluoroalkylamino)phenyl compounds

ABSTRACT

This disclosure describes novel 4-(polyfluoroalkylamino)phenyl compounds useful as hypolipidemic and antiatherosclerotic agents.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds and, more particularly,is concerned with 4-(polyfluoroalkylamino)substituted phenyl compoundswhich may be represented by the following structural formula ##STR1##wherein R₁ is a saturated or unsaturated hydrocarbon radical of 7-19carbon atoms which may be branched or unbranched and which may contain asaturated or unsaturated cycloalkyl group, said radical containing oneor more perfluorinated (--CF₂ -- or --CF₃) carbon atoms excluding thecarbon adjacent to the nitrogen atom; R₂ is selected from the groupconsisting of hydrogen or a group convertible in vivo thereinto such asmethyl, carboxymethyl, acetyl, succinyl, 1-(sodiumsulfo)loweralkyl,1-(sodiumsulfo)polyhydroxyalkyl, and 3-aryl-1,3-bis-(sodiumsulfo)alkyl;and

(a) J is ##STR2## Z being selected from the group consisting ofhydrogen, loweralkyl, hydroxy, loweralkoxy, loweralkoxyloweralkoxy,diloweralkylaminoloweralkoxy, (mono- or polyhydroxy)loweralkoxy,allyloxy, 2,3-epoxypropoxy, substituted or unsubstituted benzyloxy,substituted or unsubstituted phenoxy and 3-pyridyloxy, pyridylmethoxy,(mono- or polycarboxy)loweralkoxy, (mono- orpolycarboxy)hydroxyloweralkoxy, tetrahydropyranyloxy, (mono- orpolyhydroxy)alkylamino, allylamino, propargylamino, 2-sulfoethylamino,(mono- or polycarboxy)loweralkylamino, (mono- orpolycarboalkoxy)loweralkylamino, loweralkanoylamino, (substituted orunsubstituted)aroylamino, loweralkanesulfonylamino, (substituted orunsubstituted)arenesulfonylamino, loweralkanoylhydrazino, hydroxylamino,polymethyleneimino, (4-carboethoxy- or 4-carboxy)thiazolidino,loweralkyl bearing one or more carboxy, carboalkoxy, carbamoyl, acyl,sulfinyl, or sulfonyl groups, or

(b) J is carboxyloweralkyl, carboxyloweralkenyl, carboxyloweralkynyl,carboalkoxyloweralkyl, carboalkoxyloweralkenyl, carboalkoxyloweralkynyl;and the pharmaceutically acceptable non-toxic acid-addition and cationicsalts thereof. Lower whenever applied to alkyl, alkanoyl,alkanesulfonyl, alkoxy, alkenyl or alkynyl refers to a chain of 1-6carbon atoms which may be branched or unbranched. The polyhydroxy andpolycarboxy groups referred to above contain 2 to 4 hydroxy or carboxygroups, respectively.

Suitable groups contemplated by the present invention for thepolyfluorinated substituent R₁ are, for example,6-(trifluoromethyl)hexyl, 8-(trifluoromethyl)octyl,10-(trifluoromethyl)decyl, 11-(trifluoromethyl)undecyl,13-(trifluoromethyl)tridecyl, 15-(trifluoromethyl)pentadecyl,17-(trifluoromethyl)heptadecyl, 1-(2,2,2-trifluoroethyl)decyl,1-(2,2,2-trifluoroethyl)pentadecyl, 7-(trifluoromethyl)undecyl,1-hexyl-11-(trifluoromethyl)undecyl, 3,7-dimethyl-7-(trifluoromethyl)octyl, 11-(pentafluoroethyl)undecyl,16-(pentafluoroethyl)hexadecyl, 11-(heptafluoropropyl)undecyl,11-(heptafluoroisopropyl)undecyl, 11-(nonafluorobutyl)undecyl,11-(undecafluoropentyl)undecyl,12-fluoro-12-(heptafluoropropyl)-12-(trifluoromethyl)dodecyl,5-(pentadecafluoroheptyl)pentyl, 7-(pentadecafluoroheptyl)heptyl,3,3-difluorotetradecyl, 6,6-difluorohexadecyl, 11,11-difluorododecyl,14,14-difluoropentadecyl, 15,15-difluorohexadecyl,16,16-difluoroheptadecyl, 11,11-difluoro-16-(trifluoromethyl)hexadecyl,(pentadecafluoroheptyl)methyl, (hentricontafluoropentadecyl)methyl,11-(trifluoromethyl)-9-undecenyl, 15-(trifluoromethyl)-9-pentadecenyl,5-(pentadecafluoroheptyl)-4-pentenyl,6-(pentadecafluoroheptyl)-5-hexenyl,15-(trifluoromethyl)-7-pentadecenyl,15-(trifluoromethyl)-12-pentadecenyl,15-(trifluoromethyl)-4-pentadecynyl,1-hexyl-9-(trifluoromethyl)-4-nonynyl,3-(2,2,2-trifluoroethyl)-2,4,4-trimethylcyclopentyl,3-(trifluoromethyl)-2,4,4-trimethylcyclohexyl, and the like.

Suitable esters contemplated by the present invention are those in whichthe group Z is methoxy; isopropoxy; 2-ethoxyethoxy;2-dimethylaminoethoxy; 1-methyl-4-piperidyloxy; 4-pyridylmethoxy;2,3-dihydroxypropoxy; 2-hydroxypropoxy; 3-hydroxypropoxy;4-chlorobenzyloxy; 3-methylbenzyloxy; 4-sulfophenoxy; 4-fluorophenoxy;2,6-dichlorophenoxy; 3-carboxyphenoxy; 2,6-dimethyl-3-pyridyloxy;6-methoxy-3-pyridyloxy; 2-hydroxy-3-pyridyloxy; 5-carboxy-3-pyridyloxy;4-cyano-3-pyridyloxy; carboxymethoxy; 1-methoxycarbonylpropoxy;2-methoxycarbonyl-2-propyl and the like.

Suitable amides contemplated are those in which the group Z is2,3-dihydroxypropylamino; carboxymethylamino, acetylamino, benzoylamino,4-chlorobenzoylamino; methanesulfonylamino; phenylsulfonylamino,1-piperidyl, and the like.

Suitable keto-acids and keto-esters contemplated by the presentinvention are those in which the radical Z is selected from the groupconsisting of carboxymethyl carboxyethyl; 2-carboethoxy-2-propyl;dicarboethoxymethyl; carboethoxyvinyl and the like. Suitable alkanoic,alkenoic acid alkynoic acids and esters are those in which the radical Jis selected from the group consisting of 4-carboxybutyl;2-carboethoxyethyl; 2-carboxyvinyl, 2-carboethoxyethynyl, and the like.

The invention also pertains to novel compositions of matter useful asantiatherosclerotic agents and to methods of amelioratingatherosclerosis by counteracting hyperlipemia and arterial plaqueformation in mammals therewith; the active ingredients of saidcompositions of matter being the novel 4-(polyfluoroalkylamino)phenylcompounds of the present invention. These compounds may be utilizedeither as such or in the form of a pharmaceutically acceptable salt withan organic or inorganic acid or base. The invention also contemplates amethod for lowering serum lipids and for ameliorating atherosclerosis inmammals by the administration of said compounds.

BACKGROUND OF THE INVENTION

Considerable effort has been directed in recent years to obtainsubstances useful in counteracting the consequences of hyperlipidemia, acondition involving elevated cholesterol, phospholipid and/ortriglyceride levels in the blood, and of hyperlipoproteinemia, involvingan imbalance of the lipoproteins. The most serious condition associatedwith hyperlipidemia and hyperlipoproteinemia is atherosclerosis, a formof arteriosclerosis characterized by lipid accumulation and thickeningof the walls of both medium-sized and large arteries such as the aorta.Their walls are thereby weakened and the elasticity and effectiveinternal size of the arteries decreased. Atherosclerosis, the mostcommon cause of coronary artery disease, is of great medical importancesince it tends to occlude those arteries supplying blood to the heartmuscles and brain, thereby producing permanent damage to these organs.Such damage may lead to ischemic heart disease, congestive heartfailure, life-threatening arrhythmias, senility, or stroke. Involvementof leg arteries may lead to gangrene and loss of the limb. It has beenknown for more than 100 years that cholesterol is a major component ofatherosclerotic lesions or plaques. Investigators have been trying todetermine the role of cholesterol in lesion initiation and developmentand also, most importantly, whether lesion formation can be prevented orreversed and enlargement of lesions be slowed or stopped. The earliestlesions are known to be fatty streaks, largely of cholesterol, whichoften progress in stages to plaques containing cellular, fibrous andcalcified material in addition to the lipids.

The evidence that hyperlipidemia is one of the factors involved incoronary heart disease is very impressive. A most important studycarried out in Framingham, Mass. (Gordon and Verter, 1969) in over 5,000persons for more than 12 years established a correlation between highconcentrations of blood cholesterol and increased risk or heart attack.Although the causes of coronary artery disease are multiple, one of themost constant factors has been the elevated concentration of lipids inthe blood plasma. A combined elevation of cholesterol and triglycerideshas been shown (Carlson and Bottiger, 1972) to carry the highest risk ofcoronary heart disease. The majority of patients with ischemic heartdisease or peripheral vascular disease were found to havehyperlipoproteinemia, involving very low-density and/or low-densitylipoproteins (Lewis et al., 1974).

The reason for most treatment of hyperlipidemia or hyperlipoproteinemiais for arresting, reversing or preventing atherosclerosis. In the past,attempts have been made to lower the levels of cholesterol,phospholipids, and triglycerides in the blood by the oral feeding ofvarious substances which have been generally referred to in the art ashypolipidemic agents or hypocholesteremic adjuvants. Typical of suchsubstances are lecithin, pectin, cottonseed oil, and the mucilaginoussubstances listed in U.S. Pat. No. 3,148,114. In addition, severalsynthetic hypolipidemic agents are now available, namely, clofibrate,D-thyroxine, cholestyramine, and nicotinic acid [Levy and Frederickson,Postgraduate Medicine 47, 130 (1970)]. Clofibrate has the undesirableside-effect of causing hypertrophy of the liver in some patients.

The development of agents capable of reducing elevated blood lipids andof favorably altering blood-lipoprotein patterns is considered bymedical authorities to be extremely important for the treatment andprevention of atherosclerosis. 4-(Alkylamino)benzoic acids and estersare the subject of our U.S. Pat. No. 3,868,416 issued Feb. 25, 1975.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are new and novel4-(polyfluoroalkylamino)phenyl compounds and have useful biological andpharmacological properties. No hypolipidemic activity has been reportedin the literature for these compounds and they are different instructure from other hypolipidemic agents. The compounds of thisinvention lower serum-lipid concentrations and also minimize atheromaformation in the aorta. These compounds provide the oral administrationrequired of hypolipidemic agents, which patients usually take for manyyears. The novel compounds of this invention are adequately and reliablyabsorbed from the gastrointestinal tract with little, if any,gastrointestinal irritation.

We have now found that certain members of this class of compound cansafely and effectively lower both serum sterols and triglycerides inwarm-blooded animals. Such actions on serum-lipid components areconsidered to be very useful in the treatment of atherosclerosis,especially in contrast to available drugs whose action is much morelimited. For some time it has been considered desirable to lowerserum-lipid levels and to correct lipoprotein imbalance in mammals as apreventive measure against atherosclerosis. The compounds of the presentinvention do not act by blocking late stages of cholesterol biosynthesisand thus do not produce accumulation of intermediates such asdesmosterol, as equally undesirable as cholesterol itself. Compoundswith the combination of therapeutically favorable characteristicspossessed by those of the present invention can be safely administeredto warm-blooded mammals for the treatment of hyperlipidemic andatherosclerotic states found in patients with or prone to heart attacks,to peripheral or cerebral vascular disease, and to stroke.

The 4-(polyfluoroalkylamino)phenyl compounds of the present inventionare, in general, white crystalline solids having characteristic meltingpoints and absorption spectra. They are soluble in organic solvents suchas lower alkanols, chloroform, toluene, dimethylformamide, and the likebut are generally not very soluble in water.

The novel compounds of the present invention which are organic bases maybe converted to their non-toxic acid-addition salts with a variety ofpharmaceutically acceptable organic and inorganic salt-forming reagents.Thus, acid-addition salts may be formed by admixture of the organic freebase in a neutral solvent with one or two equivalents of an acid such assulfuric, phosphoric, hydrochloric, hydrobromic, trifluoroacetic,citric, tartaric, ascorbic, and the like.

The novel compounds of the present invention in their acidic forms arethose which contain acidic substituents are converted to their organicor inorganic cationic salts for therapeutic use. The sodium or potassiumsalts which are formed in solution in the course of hydrolysis of theiresters can be isolated as the solid alkali metal salts by cooling. Whereit is desirable to purify a compound in the form of the acid, the saltis conveniently formed by treating its solution w-th exactly oneequivalent of base and evaporation of lyophilization. Alkaline earthsalts are prepared similarly, often using their acetate salts as aconveniently soluble form. Organic base salts such as those ofN-methylglucamine are prepared by dissolving equimolar amounts of theacid and the base in hot ethanol or aqueous alcohols and cooling tocrystallization.

Many of the polyfluorinated-alkyl halides required as intermediates forthe syntheses of the novel 4-(polyfluoroalkylamino)phenyl compounds ofthe present invention are prepared from the corresponding hydroxy acids,for example, reaction of 16-hydroxyhexadecanoic acid with hydrogenbromide followed by sulfur tetrafluoride affords15-(trifluoromethyl)pentadecyl bromide. Certain of thepolyfluorinated-alkyl halides or methanesulfonates are prepared from thecorresponding alcohols which in turn are obtained from the appropriatepolyfluorinated carboxylic acids, for example, reduction of11-(pentafluoroethyl)undecanoic acid with diborane or a metal hydrideaffords 11-(pentafluoroethyl)undecanol which may then be converted to11-(pentafluoroethyl)undecyl bromide by reaction with hydrogen bromideor alternatively to 1-(methanesulfonyloxy)-11-(pentafluoroethyl)undecaneby reaction with methanesulfonyl chloride. Other polyfluorinated-alkylhalides are prepared by the reaction of sulfur tetrafluoride withketones, for example, reaction of 17-bromo-11-oxoheptadecanoic acid(obtained by the peroxide-catalyzed addition of hydrogen bromide to11-oxo-16-heptadecenoic acid) with sulfur tetrafluoride affords16-(trifluoromethyl)-11,11-difluorohexadecyl bromide. Similarly,15-bromo-2-pentadecanone (obtained by alkylation of14-bromotetradecanoyl chloride with dimethyl cadmium) yields14,14-difluoropentadecyl bromide.

Many of the novel 4-(polyfluoroalkylamino)phenyl compounds of thepresent invention may be prepared by reaction of the appropriate4-aminophenyl compound with a suitable alkylating agent such as an alkylhalide, sulfate, tosylate, or trifluoromethanesulfonate with or withouta solvent at 30° C. to 150° C. Appropriate 4-aminophenyl compounds are,for example, ethyl 4-aminobenzoate; 2,3-dihydroxypropyl 4-aminobenzoate;phenyl 4-aminobenzoate; 1-(4-aminobenzoyl)pyrrolidine; and ethyl4-(4-aminophenyl)butyrate. Suitable solvents are loweralkanols,N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dimethoxyethane,acetonitrile, toluene, benzene, hexamethylphosphoramide and the like.The reaction may be carried out with two equivalents of the4-aminophenyl compound or with one equivalent of the compound plus oneequivalent of a base such as an alkali carbonate or bicarbonate or anunreactive organic base such as diisopropylethylamine or alternativelywith a catalytic amount of copper powder when an alkyl halide is used asthe alkylating agent. Similarly, alkylation of the sodium salt (formedwith sodium hydride) of either the amino group of a 4-aminophenylcompound or the anilide moiety of a 4-(acetylamino)phenyl compoundyields the novel 4-(polyfluoroalkylamino)phenyl compounds or an N-acetylderivative thereof. Removal of the N-acetyl group by conventionalhydrolytic methods affords the desired 4-(polyfluoroalkylamino)phenylcompounds.

Alternative methods of preparation of these compounds are by reductivealkylation of a 4-aminophenyl compound, which may be generated in situby reduction of a 4-aminophenyl precursor such as a 4-nitrophenylcompound and the like or by a metal hydride reduction of a4-(acylamino)phenyl compound. For example,15-(trifluoromethyl)pentadecanal or another carbonylalkane and4-aminobenzoic acid are reduced under 1-10 atmospheres of hydrogen usingan activated metal catalywt or with a metal hydride such as sodiumborohydride forming 4-[15-(trifluoromethyl)pentadecylamino]benzoic acidand the like. Diborane reduction of 4-(polyfluoroalkanoylamino)phenylcompounds such as ethyl4-[15-(trifluoromethyl)pentadecanoylamino]benzoate at room temperatureor above for 1-6 hours yields the corresponding4-(polyfluoroalkylamino)phenyl compounds such as ethyl4-[15-(trifluoromethyl)pentadecylamino]benzoate. The4-(polyfluoroalkanoylamino)phenyl compounds used in these reductions areprepared by acylation of the appropriate 4-aminophenyl compounds withsuitable acylating agents, such as polyfluoroalkanoyl halides. Toprepare the 4-(polyfluoroalkylamino)phenyl alkenoic and alkynoic acidsit is advantageous to form the corresponding polyfluoroalkylchloroimidefrom the 4-(polyfluoroalkanoylamino)phenyl compounds using phosphorusoxychloride and base, and then reduce the polyfluoroalkylchloroimidemoiety to a polyfluoroalkylamino group with sodium borohydride.

A method useful for the introduction of the polyfluoroalkylamino groupinto aromatic compounds is neucleophilic aromatic substitution. Anexample of this method is the reaction of15-(trifluoromethyl)pentadecylamine (or the anion derived therefrom bytreatment with a strong base) with ethyl 4-fluorobenzoate to yield ethyl4-[15-(trifluoromethyl)pentadecylamino]benzoate. In certain instances anamine such as 15-(trifluoromethyl)pentadecylamine may be reacted with abenzyne such as that derived from ethyl 4-bromobenzoate by treatmentwith sodium amide to yield the 4-(polyfluoroalkylamino)phenyl compound,in this case ethyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate.

The 4-(polyfluoroalkylamino)benzoic, benzoylalkanoic, and phenylalkanoicacids of this invention are often prepared from the correspondingp-aminobenzoic, benzoylalkanoic, and phenylalkanoic acids by thesequence involving esterification of the amino acid with ethanol in thepresence of boron trifluoride etherate, followed by alkylation of theamino function by the methods above. The free acids are then liberatedby hydrolysis of the ester with aqueous alcoholic sodium hydroxide at80° for 2-10 hours followed by acidification. The acids obtained by thisprocedure may be converted to the corresponding metallic cationic salts.For example, the sodium salt may be prepared by reaction of the acidwith sodium hydroxide in a mixture of ethanol and water.

Alternatively, the acids of this invention may be prepared by hydrolysisof the corresponding nitriles or various amides, imidates or oxazolines.The carboxylic acid moiety may also be generated by oxidation of thecorresponding aldehydes, acetophenones, benzyl alcohols, or toluenes,most often with the use of an amine-protecting group such astrifluoroacetyl or t-butyloxycarbonyl.

The carboxaldehydes of this invention may be prepared by several methodsamong which is alkylation of the corresponding acetal by the methodsabove followed by hydrolysis of the resulting4-(polyfluoroalkylamino)phenyl acetal to the desired aldehyde. Aldehydesmay also be prepared by reduction of the appropriate nitriles. Forexample, treatment of4-[15-(trifluoromethyl)pentadecylamino]benzonitrile with stannicchloride and anhydrous hydrogen chloride gas, followed by hydrolysis inhot water provides 4-[15-(trifluoromethyl)pentadecylamino]benzaldehyde.These reductions are also conveniently carried out with hydrides such asdiisobutyl aluminum hydride.

The novel esters and amides of the present invention may readily beprepared by treating a derivative of the corresponding carboxylic acid,such as the acid halide, mixed acid anhydride or activated ester oramide with the appropriate alcohol or amine, respectively. Thesereactions may be carried out in an inert solvent at a temperature of50°-125° C. for 30 minutes to 18 hours or more. In the case of the acidhalide and other acid-forming acylating agents, the reaction is carriedout in the presence of an acid scavenger such as diisopropylethylamine;4-dimethylaminopyridine; pyridine; triethylamine; finely powdered sodiumcarbonate and the like. A protecting group on the amino nitrogen is usedfor best results. The simplest protecting group is provided byprotonation of the amine to yield an anilinium salt prior to or duringformation of the acylating form of the carboxyl group. Acylation of theamino group by carefully selected acyl groups such as carbobenzyloxy,carbo-t-butoxy, and trifluoroacetyl provides protection of this groupfrom self-acylation during amide or ester formation. These protectinggroups are then removed by catalytic hydrogenation, mild acid treatment,and mild alkali treatment, respectively. Other N-acyl protecting groupssuch as acetyl and succinoyl may be used and these are removed byconventional methods. Activated esters and amides, useful to synthesizethe esters and amides of the present invention, are those containingcarboxymethyl, 4-nitrophenyl, N-oxysuccinimide and 1-imidazolyl groupsand the like. In certain cases, treatment of the acids with an excess ofan appropriate hydroxy-containing substrate in the presence of a Lewisor mineral acid such as boron trifluoride, sulfuric acid or hydrochloricacid affords the corresponding esters. Ordinary esters such as themethyl and ethyl esters are sufficiently reactive to form the amides ofthe 4-(polyfluoroalkylamino)benzoic acids and highly reactive aminesubstrates such as hydroxylamine, hydrazines and certain alkyl primaryamines. With certain kinds of substrates in order to form amides it isnecessary to first form the alkali metal or strong organic base salts ofthese substrates prior to reacting them with the various aforementionedacylating forms of the 4-(polyfluoroalkylamino)benzoic acids. Forexample, the aminoalkanecarboxylic and aminoalkanesulfonic acids arezwitterionic and must be converted to their salts, suitably in situ.They may also be used in the form of their esters and then hydrolyzedafter amide formation. Certain substrates which are neutral, like thecarboxamides, or slightly acidic, like the alkane or arene sulfonamides,are converted to reactive sodium salts by reaction with sodium hydrideor other basic reagents.

The α-substituted 4-(polyfluoroalkylamino)acetophenones of the inventionare prepared by reaction of a derivative of the appropriate benzoicacid, such as 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloridehydrochloride, with two or more equivalents of the reactive salt of anacidic methylene compound, for example the sodium salt of diethylmalonate. Other benzoic acid derivatives are also suitable for thisreaction, such as 4-[N-trifluoroacetyl(polyfluoroalkyl)amino]benzoylchloride, a 4-[N-tert-butyloxycarbonyl(polyfluoroalkyl)amino]benzoylchloride or a methyl 4-(polyfluoroalkylamino)benzoate ester. In somecases the final step in the preparation of the α-substituted4-(polyfluoroalkylamino)acetophenones is the removal of thenitrogen-protecting group. In other cases, hydrolysis of one or more ofthe ester groups in the acylation product affords an unstablepolycarboxylic acid which undergoes decarboxylation to allow thepreparation of another acetophenone derivative. For example, thereaction of tert-butyl ethyl4-[15-(trifluoromethyl)pentadecylamino]benzoylmalonate withtrifluoroacetic acid affords ethyl4-[15-(trifluoromethyl)pentadecylamino]benzoylacetate. In other cases,hydrolysis of one or more of the ester groups allows the preparation ofthe corresponding acid derivative. For example, the hydrolysis of ethyl4-[15-(trifluoromethyl)pentadecylamino]benzoylacetate yields4-[15-(trifluoromethyl)pentadecylamino]benzoylacetic acid.

An alternative procedure for preparing certainα-substituted-4-(polyfluoroalkylamino)acetophenones is alkylation of thecorresponding 4-aminoacetophenone by the methods above. For example,alkylation of methyl 3-(4-aminobenzoyl)propionate with15-(trifluoromethyl)bromide yields methyl3-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}propionate. Therelated carboxylic acids are then obtained by hydrolysis. Certain ofthese acids are particularly useful for the preparation of[4-(polyfluoroalkylamino)phenyl]alkanoic acids by reduction. Forexample, the Clemmensen or Wolff-Kishner reduction of3-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}propionic acid yields4-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}butyric acid.

The [4-(polyfluoroalkylamino)phenyl]alkenoic acids may be prepared bycondensation of the appropriate aldehydes or by dehydration of thecorresponding substituted-phenyl-hydroxyalkanoic acids. For example,ethyl5-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-2,4-pentadienoate isobtained by the Wittig reaction of4-[15-(trifluoromethyl)pentadecylamino]benzaldehyde with the Wittigreagent, triethyl 4-phosphonocrotonate. Alternatively, these alkenoicacids are obtained by heating 4-[N-polyfluoroalkyl-N-(methyl oracetyl)amino]benzaldehydes with the sodium salt of the carbanion ofethyl acetate or with a mixture of ethyl acetate, acetic anhydride andpotassium acetate. The second method is illustrated by dehydration ofethyl3-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-3-hydroxypropionate toyield ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate.

The acetylenic analogs are prepared by dehydrobromination of theside-chain vic-dibrominated alkanoic acid. For example,dehydrobromination of ethyl3-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-2,3-dibromopropionate,its isomers or N-acyl analogs yields ethyl3-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}propiolate. Theacetylenic acids are also formed from(4-polyfluoroalkylamino)phenylacetylene metal salts by carboxylationwith carbon dioxide. The 4-(polyfluoroalkylamino)phenylacetylenes arealso used by N-acylating with t-butyl azidoformate followed byconversion to the lithium acetylide salt and subsequent reaction of thelithium salt with boron trifluoride etherate in tetrahydrofuran at -20°C. to form tris-[4-(polyfluoroalkylamino)phenylethynyl]boranes. Thetetrahydrofuran solution of the borane is in turn reacted with ethyldiazoacetate, followed by water to yield ethyl4-[4-(polyfluoroalkylamino)phenyl]butynoate.

The 4-(polyfluoroalkylamino)phenylalkanoic acids, amides, or esters arealso prepared by catalytic reduction at 1 to 10 atmospheres of hydrogenof the corresponding alkenoic or alkynoic derivatives.

The 4-(polyfluoroalkylamino)phenylalkenoic acids and derivatives areprepared by Friedel-Crafts acylation of the N-acyl-N-alkylanilines withthe appropriate dicarboxylic acid anhydride or half acid chloride. The4-(polyfluoroalkylamino)benzoylalkanoic acids or esters, obtained bythis and by other syntheses, may be converted to the4-(polyfluoroalkylamino)phenylalkanoic acids by reduction with (a)hydrazine and alkali in diethylene glycol at 140° for 3 hours, (b) zincamalgam and ethanolic hydrochloric acid at 60° for 5 hours, (c) redphosphorus and hydriodic acid, or (d) ketalization with1,2-ethanedithiol followed by Raney nickel desulfurization. The amidesof the 4-(polyfluoroalkylamino)phenylalkanoic acids are prepared byheating the corresponding 4-(polyfluoroalkylamino)phenyl alkyl ketoneswith aqueous alcoholic ammonium polysulfide followed by hydrolysis toyield the acids with the same number of carbon atoms as the ketone.These acids are also prepared by reacting4-(N-t-butyloxycarbonyl-N-polyfluoroalkylamino)phenylmagnesium halideswith 2-(3-halopropyl)-2-oxazolines, followed by mild acid removal of2-oxazolinyl and t-butoxycarbonyl protecting groups. Similarly, theabove Grignard reagent can be reacted with3-bromotriethylorthopropionate in the presence ofdilithiumtetrachlorocuprate to yield the desired acids after removal ofthe protecting groups from the amino and carboxyl groups.

The novel compounds of the present invention are not only potenthypolipidemic agents but also prevent or diminish the formation orenlargement of arterial plaques in mammals when administered in amountsranging from about one milligram to about 250 mg. per kilogram of bodyweight per day. A preferred dosage regimen for optimum results would befrom about 5 mg. to about 100 mg. per kologram of body weight per day,and such dosage units are employed that a total of from about 0.35 gramto about 7.0 grams of the active compound, for a subject of about 70 kg.of body weight, are administered in a 24-hour period. This dosageregimen may be adjusted to provide the optimum therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation. A decided practical advantage of this inventionis that the active compound may be administered in a convenient mannerby the oral route. The compounds of the present invention exert a morepowerful hypocholesteremic and antiatherosclerotic effect than theaforementioned adjuvants and synthetic medicaments. It is not known howthese novel compounds operate in the blood serum and no theory of whythese compounds so operate is advanced. It is not intended that thepresent invention should be limited to any particular mechanism ofaction of lowering serum lipids or of ameliorating atherosclerosis, orbe limited to compounds acting by only one mechanism.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsules, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compounds may be incorporated with excipientsand used in the form of ingestible tablets, buccal tablets, troches,capsules, elixirs, suspensions, syrups, wafers, and the like. Suchcompositions and preparations should contain at least 0.1% of activecompound. The percentage of the compositions and preparations may, ofcourse, be varied and may conveniently be between about 2 to about 60%of the weight of the unit. The amount of active ingredient in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage-unit form containsbetween about 50 and 250 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring. When thedosage-unit form is a capsule, it may contain, in addition to materialsof the above type, a liquid carrier. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance, tablets, pills or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye, and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage-unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed. In addition, the active ingredients may be incorporated intosustained-release preparations and formulations.

The invention will be described in greater detail in conjunction withthx following specific Examples.

EXAMPLE 1 16-Bromohexadecanoic acid

A mixture of 18 g. of 16-hydroxyhexadecanoic acid and 160 g. of 30-34%hydrogen bromide in acetic acid is treated with 32 ml. of concentratedsulfuric acid and stirred at ambient temperature for 18 hours. Thesolution is stirred under reflux for 7 hours and then poured into 500ml. of ice-water and filtered. A methylene chloride solution of theproduct is Darco clarified, dried over magnesium sulfate, andevaporated. Crystallization of the residue from ether-petroleum etherand then acetonitrile affords 16-bromohexadecanoic acid as a whitesolid.

EXAMPLE 2 15-(Trifluoromethyl)pentadecyl bromide

A 25.0 g. quantity of 16-bromohexadecanoic acid is placed in a 2 literstainless steel bomb and after flushing with nitrogen and cooling thebomb in dry-ice, 66 g. of sulfur tetrafluoride is introduced and thesealed bomb is heated with shaking at 118° C. for 6 hours. The bomb isallowed to cool and opened and volatile material is allowed toevaporate. The residue is partitioned between water and ether and theether layer is separated, dried over anhydrous magnesium sulfate andevaporated. The residue is distilled to yield15-(trifluoromethyl)pentadecyl bromide as a clear, colorless liquid.

EXAMPLE 3 (Pentadecafluoroheptyl)(trifluoromethanesulfonyloxy)methane

A mixture of 40 g of (pentadecafluoroheptyl)methanol, 11 g. oftriethylamine, and 200 ml. of methylene chloride is stirred at -20° C.while a solution of 18 g. of trifluoromethanesulfonyl chloride in 50 ml.of methylene chloride is added. The solution is stirred for one hour atroom temperature and then washed with ice-cold 10% hydrochloric acid,saturated aqueous sodium bicarbonate solution, and water; dried overanhydrous magnesium sulfate; and evaporated. The residual brown liquidis distilled to yield the product as a colorless liquid.

EXAMPLE 4 11-(Pentafluoroethyl)undecanol

A solution of 5 g. of 11-(pentafluoroethyl)undecanoic acid in 20 ml. oftetrahydrofuran is stirred at 0° C. while 16 ml. of 1M borane intetrahydrofuran is added during 15 minutes. The mixture is stirred for18 hours at ambient temperature, poured into ice-water, and extractedwith ether. The dried extract is evaporated and the residual oilcrystallized from hexane to yield 11-(pentadecafluoroethyl)undecanol asa white solid.

EXAMPLE 5 11-(Pentafluoroethyl)-1-(methanesulfonyloxy)undecane

To a solution of 15 g. of 11-(pentafluoroethyl)undecanol andtriethylamine (14 ml.) in dry methylene chloride (320 ml.) at -8° C. isadded methanesulfonylchloride (5.73 ml.), dropwise. The reaction mixtureis stirred at -10° C. for 30 minutes and then diluted with methylenechloride, extracted with ice-water (250 ml.), followed by cold 10%hydrochloric acid (200 ml.); cold saturated sodium bicarbonate (200 ml.)and cold saturated sodium chloride solution (200 ml.). The organic layeris separated, dried over anhydrous magnesium sulfate, and evaporated toyield the methanesulfonate as a light yellow oil.

EXAMPLE 6 6-Oxohexadecyl bromide

The Grignard reagent prepared from 60 g. of decyl bromide, 5.6 g. ofmagnesium, and 200 ml. of ether is treated with 27 g. of cadmiumchloride and the solution is stirred under reflux for 30 minutes. Thesolvent is replaced by distillation with toluene, and the toluenesolution is treated with 29 g. of 6-bromohexanoyl chloride and stirredunder reflux for 30 minutes. The mixture is cooled, diluted with 200 ml.of 10% sulfuric acid, and extracted with ether. The extracts are driedand evaporated and the residual oil distilled in vacuo to yield6-oxohexadecyl bromide as a light yellow oil.

EXAMPLE 7 6,6-Difluorohexadecyl bromide

In the manner of Example 2, 6-oxohexadecyl bromide is converted to6,6-difluorohexadecyl bromide.

EXAMPLE 8 Ethyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate

A mixture of 18.5 g. of 15-(trifluoromethyl)pentadecyl bromide, 17.0 g.of ethyl 4-aminobenzoate, 7.1 g. of potassium carbonate, and 75 ml. ofhexamethylphosphoramide is stirred for 16 hours at 120° C., allowed tocool, diluted with water, and filtered. The solid is dissolved inmethylene chloride and the solution is dried over anhydrous magnesiumsulfate and evaporated. The residual brown oil is crystallized fromethanol and recrystallized from acetonitrile to yield the product as awhite solid.

EXAMPLE 9 4-[15-(Trifluoromethyl)pentadecylamino]benzoic acid

A mixture of 6.0 g. of ethyl4-[15-(trifluoromethyl)pentadecylamino]benzoate, 4.0 g. of potassiumhydroxide and 50 ml. of ethanol is stirred at 80° C. for 4 hours. Themixture is diluted with water and adjusted to pH 5.5 by the addition ofconcentrated hydrochloric acid. Cooling and filtration affords a solidwhich is recrystallized from acetone to yield the product as a whitesolid.

EXAMPLE 10 Ethyl 4-[(pentadecafluoroheptyl)methylamino]benzoate

A solution of 45 g. of(pentadecafluoroheptyl)(trifluoromethanesulfonyloxy)methane and 28 g. ofethyl 4-aminobenzoate in 50 ml. of hexamethylphosphoramide is stirred at120° C. for 72 hours, diluted with water, and filtered. A methylenechloride solution of the solid is dried over anhydrous magnesium sulfateand evaporated. The residue is recrystallized from acetonitrile to yieldthe product as a white solid.

EXAMPLE 11 4-[(Pentadecafluoroheptyl)methylamino]benzoic acid

Hydrolysis of ethyl 4-[(pentadecafluoroheptyl)methylamino]benzoate bythe method of Example 9 affords4-[(pentadecafluoroheptyl)methylamino]benzoic acid as a white solid.

EXAMPLE 12 Ethyl 4-[11-(pentafluoroethyl)undecylamino]benzoate

A solution of 18.1 g. of11-(pentafluoroethyl)-1-(methanesulfonyloxy)undecane and 19.8 g. ofethyl p-aminobenzoate in hexamethylphosphoramide is heated at 120° C.for 20 hours. After cooling, the reaction mixture is diluted withethanol:water (1:1) (30 ml.) and chilled. More ethanol is added, themixture is filtered and the solid residue is recrystallized from ethanolto yield the product as a white solid.

EXAMPLE 13 4-[11-(Pentafluoroethyl)undecylamino]benzoic acid

Hydrolysis of ethyl 4-[11-(pentafluoroethyl)undecylamino]benzoate in themanner of Example 9 affords 4-[11-(pentafluoroethyl)undecylamino]benzoicacid as a white solid.

TABLE I

The following benzoic acids are prepared from the corresponding benzoateesters by the method of Example 9. The requisite benzoate esters areprepared from 4-aminobenzoate esters and the appropriate halide,trifluoromethanesulfonate by the methods of Examples 8, 10, and 12,respectively. Polyfluoroalkyl halides, trifluoromethanesulfonates, andmethanesulfonates required for these reactions are prepared by themethods of Examples 1-7.

    ______________________________________                                        Example No.                                                                            Compound                                                             ______________________________________                                        14       4-[6-(Trifluoromethyl)hexylamino]benzoic acid                        15       4-[7-(Trifluoromethyl)heptylamino]benzoic acid                       16       4-[8-(Trifluoromethyl)octylamino]benzoic acid                        17       4-[9-(Trifluoromethyl)nonylamino]benzoic acid                        18       4-[10-(Trifluoromethyl)decylamino]benzoic acid                       19       4-[11-(Trifluoromethyl)undecylamino]benzoic                                   acid                                                                 20       4-[12-(Trifluoromethyl)dodecylamino]benzoic                                   acid                                                                 21       4-[13-(Trifluoromethyl)tridecylamino]benzoic                                  acid                                                                 22       4-[14-(Trifluoromethyl)tetradecylamino]benzoic                                acid                                                                 23       2-[16-(Trifluoromethyl)hexadecylamino]benzoic                                 acid                                                                 24       4-[17-(Trifluoromethyl)heptadecylamino]benzoic                                acid                                                                 25       4-[18-(Trifluoromethyl)octadecylamino]benzoic                                 acid                                                                 26       4-[1-(2,2,2-Trifluoroethyl)decylamino]benzoic                                 acid                                                                 27       4-[1-(2,2,2-Trifluoroethyl)tridecylamino]ben-                                 zoic acid                                                            28       4-[1-(2,2,2-Trifluoroethyl)pentadecylamino]-                                  benzoic acid                                                         29       4-[7-(Trifluoromethyl)undecylamino]benzoic acid                      30       4-[1-Hexyl-11-(trifluoromethyl)undecylamino]-                                 benzoic acid                                                         31       4-[3,7-Dimethyl-7-(trifluoromethyl)octylamino]-                               benzoic acid                                                         32       4-[16-(Pentafluoroethyl)hexadecylamino]benzoic                                acid                                                                 33       4-[11-(Heptafluoropropyl)undecylamino]benzoic                                 acid                                                                 34       4-[11-(Heptafluoroisopropyl)undecylamino]ben-                                 zoic acid                                                            35       4-[11-(Nonafluorobutyl)undecylamino]benzoic                                   acid                                                                 36       4-[11-(Undecafluoropentyl)undecylamino]benzoic                                acid                                                                 37       4-[12-Fluoro-12-(heptafluoropropyl)-12-(tri-                                  fluoromethyl)dodecylamino]benzoic acid                               38       4-[5-(Pentadecafluoroheptyl)pentylamino]ben-                                  zoic acid                                                            39       4-[7-(Pentadecafluoroheptyl)heptylamino]ben-                                  zoic acid                                                            40       4-(3,3-Difluorotetradecylamino)benzoic acid                          41       4-(6,6-Difluorohexadecylamino)benzoic acid                           42       4-(11,11-Difluorododecylamino)benzoic acid                           43       4-(14,14-Difluoropentadecylamino)benzoic acid                        44       4-(15,15-Difluorohexadecylamino)benzoic acid                         45       4-((16,16-Difluoroheptadecylamino)benzoic acid                       46       4-[11,11-Difluoro-16-(trifluoromethyl)hexa-                                   decylamino]benzoic acid                                              47       4-[(Hentricontafluoropentadecyl)methylamino]-                                 benzoic acid                                                         48       4-[11-(Trifluoromethyl)-9-undecenylamino]ben-                                 zoic acid                                                            49       4-[15-(Trifluoromethyl)-9-pentadecenylamino]-                                 benzoic acid                                                         50       4-[5-(Pentadecafluoroheptyl)-4-pentenylamino]-                                benzoic acid                                                         51       4-[6-(Pentadecafluoroheptyl)-5-hexenylamino]-                                 benzoic acid                                                         52       4-[15-(Trifluoromethyl)-7-pentadecenylamino]-                                 benzoic acid                                                         53       4-[15-(Trifluoromethyl)-12-pentadecenylamino]-                                benzoic acid                                                         54       4-[15-(Trifluoromethyl)-4-pentadecynylamino]-                                 benzoic acid                                                         55       4-[1-Hexyl-9-(trifluoromethyl)-4-nonynylamino]-                               benzoic acid                                                         56       4-[3-(2,2,2-Trifluoroethyl)-2,4,4-trimethyl-                                  cyclopentylamino]benzoic acid                                        57       4-[3-(Trifluoromethyl)-2,4,4-trimethylcyclo-                                  hexylamino]benzoic acid                                              ______________________________________                                    

EXAMPLE 58 4-[15-(Trifluoromethyl)pentadecylamino]benzaldehyde

A solution of 4-aminobenzonitrile (11.8 g.) and15-(trifluoromethyl)pentadecyl bromide (15.3 g.) inhexamethylphosphoramide (200 ml.) is heated under an atmosphere ofnitrogen in an oil bath maintained at 120° C. for 22 hours. The reactionmixture is cooled to room temperature and water is added gradually. Themixture is then chilled in an ice-bath and filtered. The solid is washedthoroughly with water and dried. The solid is recrystallized fromether-hexane to yield4-[(15-trifluoromethyl)pentadecylamino]benzonitrile as a pale yellowsolid.

Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is addedwith stirring to a solution of the nitrile under a nitrogen atmosphere.The temperature rises to 40° C. during the addition which takes 30minutes and the reaction is then stirred for 1 hour. A solution ofmethanol in toluene (50 ml., 1:1) is added during 30 minutes and themixture is poured into vigorously stirred ice-cold aqueous sulfuric acid(500 ml., 5%). After 10 minutes, diatomaceous earth (30 g.) is added,the mixture filtered and the organic layer separated. The aqueoussolution is extracted twice with toluene (100 ml.) and the combinedorganic layers are washed with aqueous sodium bicarbonate, dried overmagnesium sulfate, decolorized with charcoal, filtered and evaporated invacuo to give a light yellow crystalline solid. Recrystallization fromhexane affords 4-[15-(trifluoromethyl)pentadecylamino]benzaldehyde as awhite solid.

TABLE II

The following benzaldehydes are prepared from 4-aminobenzonitrile andthe appropriate polyfluoroalkyl halide by the method of Example 58.

    ______________________________________                                        Example No.                                                                            Compound                                                             ______________________________________                                        59       4-[6-(Trifluoromethyl)hexylamino]benzaldehyde                        60       4-[11-(Trifluoromethyl)undecylamino]benzalde-                                 hyde                                                                 61       4-[17-(Trifluoromethyl)heptadecylamino]ben-                                   zaldehyde                                                            62       4-[7-(Trifluoromethyl)undecylamino]benzaldehyde                      63       4-[11-(Pentafluoroethyl)undecylamino]benzalde-                                hyde                                                                 64       4-[16-(Pentafluoroethyl)hexadecylamino]ben-                                   zaldehyde                                                            65       4-[5-(Pentadecafluoroheptyl)pentylamino]ben-                                  zaldehyde                                                            66       4-(6,6-Difluorohexadecylamino)benzaldehyde                           67       4-(14,14-Difluoropentadecylamino)benzaldehyde                        68       4-[(Pentadecafluoroheptyl)methylamino]benzal-                                 dehyde                                                               69       4-[(Hentricontafluoropentadecyl)methylamino]-                                 benzaldehyde                                                         70       4-[15-(Trifluoromethyl)-12-pentadecenylamino]-                                benzaldehyde                                                         71       4-[15-(Trifluoromethyl)-4-pentadecynylamino]-                                 benzaldehyde                                                         72       4-[3-(Trifluoromethyl)-2,4,4-trimethylcyclo-                                  hexylamino]benzaldehyde                                              ______________________________________                                    

EXAMPLE 73 4-[15-(Trifluoromethyl)pentadecylamino]benzoyl chloridehydrochloride

A cold solution of 25 g. of4-[15-(trifluoromethyl)pentadecylamino]benzoic acid in 500 ml.dimethoxyethane-methylene chloride (4:1) is prepared and dryhydrochloric acid is bubbled through the solution until no moreprecipitate forms. The solution is treated with 25 ml. thionyl chlorideand refluxed until all of the precipitate has dissolved. The solventsare evaporated to yield 4-[15-(trifluoromethyl)pentadecylamino]benzoylchloride hydrochloride as an orange, semi-crystalline mass.

EXAMPLE 744-[N-Trifluoroacetyl-15(trifluoromethyl)pentadecylamino]benzoyl chloride

A stirred, ice-cold suspension of 9 g.4-[15-(trifluoromethyl)pentadecylamino]benzoic acid in 100 ml. ofdimethoxyethane and 16 ml. of pyridine is treated with 18 ml. oftrifluoroacetic anhyride at 0° C. The solution is stirred at 0° C. for30 minutes then at room temperature and then diluted with 300 ml. etherand 100 g. ice. After stirring vigorously for 15 minutes, the phases areseparated, the ether solution is washed with brine, dried and evaporatedto a white, amorphous solid.

To a solution of 9.2 g. of the above solid in 30 ml. methylene chlorideand 0.5 ml. dimethylformamide is added 5.7 ml. thionyl chloride. After20 hours at reflux, the solvents are evaporated to yield4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino]benzoylchloride as a light yellow, mobile oil.

EXAMPLE 754-[N-Carbobenzyloxy-15-(trifluoromethyl)pentadecylamino]benzoyl chloride

To 15 g. 4-[15-(trifluoromethyl)pentadecylamino]benzoic acid in 200 ml.warm chloroform is added a solution of 15 g. of sodium carbonate in 150ml. water. To the vigorously stirred solution is added 10 g.carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layersare separated, washed three times with 1N hydrochloric acid, dried, andevaporated to an oil. The oil is dissolved in 300 ml. toluene, treatedwith 15 ml. thionyl chloride and the solution is refluxed for 5 hours.The solvents are evaporated and the residue is dissolved three times intoluene, evaporating each time, ultimately to yield4-[N-carbobenzyloxy-15-(trifluoromethyl)pentadecylamino]benzoyl chlorideas a viscous, orange oil.

EXAMPLE 761-{4-[N-tert-Butyloxycarbonyl-15-(trifluoromethyl)pentadecylamino]benzoyl}imidazole

A solution of 10 g. 4-[15-(trifluoromethyl)pentadecylamino]benzoic acidin 100 ml. dioxane is treated with 4.0 g. tert-butylazidoformate and 10ml. pyridine. After stirring at room temperature for 18 hours, theprotected amido-acid is precipitated from solution by the addition of150 ml. water. The solid is collected, and thoroughly dried, anddissolved in 200 ml. of a mixture consisting of methylenechloride/dimethoxyethane/pyridine (1:4:1). To this solution is added 5.4g. 1,1'-carbonyldiimidazole. The solution is stirred overnight at roomtemperature and the solvents are evaporated to yield1-{4-[N-tert-butyloxycarbonyl-15-(trifluoromethyl)pentadecylamino]benzoyl}imidazoleas an orange oil.

EXAMPLE 77 2,3-Dihydroxypropyl4-[15-(trifluoromethyl)pentadecylamino]benzoate

A solution of 7.34 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoicacid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirredfor 24 hours at ambient temperature, diluted with 100 ml. of ether andstirred for 5 days at ambient temperature. The mixture is treated withwater and extracted with ether. The dried extracts are evaporated toyield the product as a white solid.

EXAMPLE 78 Methyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate

A solution of 7.20 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoicacid in 25 ml. of hexamethylphosphoramide is added to a stirred mixtureof 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. ofhexamethylphosphoramide. The solution which forms after one hour istreated with 11.0 g. of methyl iodide and is then stirred at 25° C. for18 hours. Dilution with water followed by filtration affords a whitesolid which is crystallized from ethanol to yield the product as a whitesolid.

EXAMPLE 79 3-Hydroxypropyl4-[15-(trifluoromethyl)pentadecylamino]benzoate

A mixture of 2.25 g. of methyl4-[15-(trifluoromethyl)pentadecylamino]benzoate, 280 mg. of1,3-propanediol and 1.37 g. of p-toluenesulfonic acid is heated at 180°C. for 18 hours and then is partitioned between ether and 3% aqueoussodium carbonate solution. The ether layer is separated, dried, andevaporated to yield the product as a white solid.

EXAMPLE 80 2-Ethoxyethyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate

A solution of 11.8 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoicacid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluorideetherate in 200 ml. of toluene is stirred under reflux for 48 hours. Thesolution is treated with an additional 5.35 ml. of boron trifluorideetherate and refluxing is continued for 120 hours. Dilution with waterand methylene chloride followed by filtration affords the product as awhite solid.

EXAMPLE 81 Isopropyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate

A solution of 50.5 g of 4-[15-(trifluoromethyl)pentadecylamino]benzoicacid and 34.4 ml. of boron trifluoride etherate in 200 ml. of isopropylalcohol is stirred under reflux for 44 hours, allowed to cool, andpoured into 1.20 liters of ice cold 5% aqueous sodium carbonatesolution. The white solid is collected by filtration and recrystallizedfrom benzene-ethanol to yield the product as a white solid.

EXAMPLE 82 1-(Methoxycarbonyl)propyl4-[15-(trifluoromethyl)pentadecylamino]benzoate

To a solution of 10.0 g. 4-[15-trifluoromethyl)pentadecylamino]benzoylchloride hydrochloride in 200 ml. methylene chloride is added dropwise asolution of 3 g. methyl α-hydroxybutyrate and 5 g. triethylamine in 100ml. ether. After 17 hours stirring at room temperature, the precipitateis collected and washed with several portions of ether. The ethersolution is washed with water, dried and evaporated to yield the productas a white solid.

EXAMPLE 83 1-(Ethoxycarbonyl)ethyl4-[15-(trifluoromethyl)pentadecylamino]benzoate

To a warm mixture of 7 g. sodium4-[15-(trifluoromethyl)pentadecylamino]benzoate in 100 ml. ethanol isadded 4.7 g. ethyl α-tosyloxypropionate. After 17 hours at reflux, thecooled solution is diluted with an equal volume of water and theresultant precipitate is filtered. After washing with cold ethanol anddrying, the product is crystallized from acetonitrile to yield theproduct as colorless crystals.

EXAMPLE 84 1-Carboxyethyl4-[15-(trifluoromethyl)pentadecylamino]benzoate

A flask containing 10.0 g.4-[15-(trifluoromethyl)pentadecylamino]benzoic acid, 3.3 g. lactic acid,500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with aSoxhlet extractor charged with activated 4 A Linde molecular sieves. Thesolution is refluxed for 24 hours, during which time the Soxhletextractor is charged twice more with fresh sieves. The hot solution isfiltered and allowed to cool, whereupon the product separates asoff-white crystals.

EXAMPLE 85 DiethylO-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}tartrate

A mixture of4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino)benzoylchloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with2.5 g. diethyl tartarate and refluxed for 24 hours. The hot solution isfiltered, the residue is washed with hot ether, and the solution isevaporated. After treatment with aqueous methanolic potassium carbonate,the product is precipitated by acidification, filtered, and dried.Crystallization from acetone yields the product as a white, crystallinesolid.

EXAMPLE 86 O-{4-[15-(Trifluoromethyl)pentadecylamino]benzoyl}malic acid

A warm solution of4-[N-carbobenzyloxy-15-(trifluoromethyl)pentadecylamino]benzoyl chlorideand 1.3 g. triethylamine in 100 ml. ether is treated with 2 g. malicacid. An immediate precipitate forms, but the mixture is refluxed forone hour and filtered while hot. The solid is washed several times withhot ether, then the ether is evaporated to yield a white solid. Theproduct is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over600 mg. 10% palladium-on-carbon at 50 psi until hydrogen uptake stops.The catalyst is filtered, and the solution is evaporated. The residue iscrystallized from acetic acid to yield the product as a white solid.

EXAMPLE 87 2-(Ethoxycarbonyl)vinyl4-[15-(trifluoromethyl)pentadecylamino]benzoate

To a mixture containing 4.3 g.1-{4-[N-tert-butyloxycarbonyl-15-(trifluoromethyl)pentadecylamino]benzoyl}imidazole,50 ml. 5 N sodium hydroxide is added 3 g. ethyl α-formyl acetate. Thesolution is vigorously stirred for 24 hours. The layers are separated,and the chloroform solution is washed once with 50 ml. 1 N sodiumhydroxide. The solvent is evaporated and the residue is heated for 30minutes at 40° C. in 50 ml. anhydrous trifluoroacetic acid. The solventis again evaporated and the oil is crystallized from acetone to yieldlight yellow crystals of the product.

TABLE III

The following benzoate esters are prepared from the carboxylic acids ofTable I (or activated derivatives thereof prepared by the methods ofExamples 73-76) by the methods of Examples 77-87 as shown in the table.

    ______________________________________                                        Example                                                                       No.    Method of Example                                                                           Compound                                                 ______________________________________                                        88     77            2,3-Dihydroxypropyl 4-[8-                                                     (trifluoromethyl)octylamino]-                                                 benzoate                                                 89     77            2,3-Dihydroxypropyl 4-[16-                                                    (pentafluoroethyl)hexadecyl-                                                  amino]benzoate                                           90     77            2,3-Dihydroxypropyl 4-[15,15-                                                 (difluoro)hexadecylamino]-                                                    benzoate                                                 91     77            2,3-Dihydroxypropyl 4-[6-                                                     (pentadecafluoroheptyl)-5-                                                    hexenylamino]benzoate                                    92     78            Methyl 4-[12-(trifluorometh-                                                  yl)dodecylamino]benzoate                                 93     78            Methyl 4-[1-hexyl-9-(trifluor-                                                omethyl)-4-nonynylamino]ben-                                                  zoate                                                    94     78            Methyl 4-[11,11-difluoro-16-                                                  (trifluoromethyl)hexadecyl-                                                   amino]benzoate                                           95     78            Methyl 4-[15,15-(difluoro)-                                                   hexadecylamino]benzoate                                  96     79            3-Hydroxypropyl 4-[15-(tri-                                                   fluoromethyl)-7-pentadecenyl-                                                 amino]benzoate                                           97     79            2-Hydroxypropyl 4-[1-(2,2,2-                                                  trifluoroethyl)pentadecyl-                                                    amino]benzoate                                           98     79            4-Hydroxybutyl 4-[12-(tri-                                                    fluoromethyl)dodecylamino]-                                                   benzoate                                                 99     79            3-Hydroxypropyl 4-[11,11-                                                     (difluoro)dodecylamio]-                                                       benzoate                                                 100    80            2-Ethoxyethyl 4-[7-(penta-                                                    decafluoroheptyl)heptylamino]-                                                benzoate                                                 101    80            3-Methoxypropyl 4-[11-(tri-                                                   fluoromethyl)undecylamino]-                                                   benzoate                                                 102    80            2-Ethoxyethyl 4-[3-(2,2,2-                                                    trifluoroethyl)-2,4,4-tri-                                                    methylcyclopentylamino]ben-                                                   zoate                                                    103    81            Isopropyl 4-[11-(trifluoro-                                                   methyl)undecylamino]benzoate                             104    82            1-(Methoxycarbonyl)propyl 4-                                                  [6-(trifluoromethyl)hexyl-                                                    amino]benzoate                                           105    82            1-(methoxycarbonyl)ethyl 4-                                                   [11-(heptafluoroisopropyl)-                                                   undecylamino]benzoate                                    106    82            1-(Ethoxycarbonyl)propyl 4-                                                   (15,15-difluorohexadecyl-                                                     amino)benzoate                                           107    82            1-(Methoxycarbonyl)propyl 4-                                                  [3-(trifluoromethyl)-2,4,4-                                                   trimethylcyclohexylamino]-                                                    benzoate                                                 108    83            1-(Ethoxycarbonyl)propyl 4-                                                   [11,11-difluoro-16-(tri-                                                      fluoromethyl)hexadecylamino]-                                                 benzoate                                                 109    83            1-(Methoxycarbonyl)ethyl 4-                                                   [11-(trifluoromethyl)undecyl-                                                 amino]benzoate                                           110    84            1-Carboxyethyl 4-[11-(hepta-                                                  fluoropropyl)undecylamino]-                                                   benzoate                                                 111    84            1-Carboxyethyl 4-[5-(penta-                                                   decafluoroheptyl)-4-pentenyl-                                                 amino]benzoate                                           112    85            Diethyl O-{4-[(hentriconta-                                                   fluoropentadecyl)methylamino]-                                                benzoyl}tartrate                                         113    85            Diethyl O-{4-( 12-fluoro-12-                                                  (heptafluoropropyl)-12-(tri-                                                  fluoromethyl)dodecylamino]-                                                   benzoyl}tartrate                                         114    85            Diethyl O-[4-(6,6-difluoro-                                                   hexadecylamino)benzoyl]tar-                                                   trate                                                    115    86            O-{4-[3,7-Dimethyl-7-(tri-                                                    fluoromethyl)octylamino]ben-                                                  zoyl}malic acid                                          116    86            O-{4-[15-(trifluoromethyl)-                                                   7-pentadecenylamio]benzoyl}-                                                  malic acid                                               117    87            2-(Ethoxycarbonyl)vinyl 4-                                                    [11-(trifluoromethyl)-9-                                                      undecenylamino]benzoate                                  118    87            2-(Ethoxycarbonyl)vinyl 4-                                                    [11-(trifluoromethyl)undecyl-                                                 amino]benzoate                                           119    87            2-(Ethoxycarbonyl)vinyl 4-                                                    [5-(pentadecafluoroheptyl)-                                                   4-pentenylamino]benzoate                                 ______________________________________                                    

EXAMPLE 120 1-{4-[15-(Trifluoromethyl)pentadecylamino]benzoyl}piperidine

To a chilled solution of 35 ml. of piperidine, 2.5 ml. of triethylamineand 0.6 g. of dimethylaminopyridine in 100 ml. of diethyl ether is added(1/2 hour) a solution of 8.3 g. of4-[15-trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in50 ml. of ether. The solution is warmed to room temperature andmaintained there for two hours. The solution is heated to reflux for anadditional 2 hours at which time the reaction is complete. The solutionis cooled, extracted twice with water and dried. The solvent is removedin vacuo and the solid is recrystallized from diethyl ether to yield theproduct as a white solid.

EXAMPLE 121 Ethyl 4-[15-trifluoromethyl)pentadecylamino]hippurate

To a solution of 18.0 g. of4-[15-(trifluoromethyl)pentadecylamino]benzoic acid in a mixture ofdioxane and methylene chloride is added gaseous hydrogen chloride for 10minutes. The slurry is cooled and 18 ml. of thionyl chloride added. Theslurry is brought to reflux for 2 hours and then concentrated undervacuum (thrice diluting with dioxane each time). The amber solution isdiluted with 100 ml. of dioxane and this solution added to freshlyprepared ethyl glycinate in 300 ml. of methylene chloride containing 1g. of dimethylaminopyridine and 10 ml. of triethylamine. After 16 hoursat room temperature the reaction is refluxed for 2 hours, cooled andfiltered. The mother liquor is extracted with water and 10% hydrochloricacid. The solution is dried and concentrated in vacuo to an amberliquid. A sample is pre-absorbed on silica and eluted with ether.Evaporation of the eluate yields a solid which is recrystallized fromacetonitrile to yield the product as a white solid.

EXAMPLE 122 N-{4-[15-(Trifluoromethyl)pentadecylamino]benzoyl}glycine

A mixture of 26.4 g. of ethyl4-[15-(trifluoromethyl)pentadecylamino]hippurate, 110 ml. of 1 N sodiumhydroxide solution; and 100 ml. of ethanol is stirred at ambienttemperature for 2 hours and then partially evaporated. The aqueoussolution is washed with diethyl ether, acidified with 6 N hydrochloricacid, and filtered. The solid is dried in vacuo and recrystallized fromacetone to yield the product as a white solid.

EXAMPLE 1234-[15-(Trifluoromethyl)pentadecylamino]-N-(phenylsulfonyl)benzamide

A solution of 31.4 g. of benzenesulfonamide in 250 ml. of drydimethylacetamide is added dropwise, with stirring and cooling, to asuspension of 5.5 g. of sodium hydride in 100 ml. of drydimethylacetamide during 30 minutes at room temperature. Stirring iscontinued for 30 minutes. In the meantime, a mixture of 36.2 g. of4-[15-(trifluoromethyl)pentadecylamino]benzoic acid in 100 ml. ofmethylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionylchloride is refluxed for 1 hour and 15 minutes. The solution isevaporated and to the resulting oil residue is added, in one portion,the previously prepared mixture of sodium benzenesulfonamide indimethylacetamide. The mixture is stirred for 30 minutes, withoutcooling, and then filtered. The filtrate is poured into 2 liters ofwater and 250 ml. of saturated sodium chloride solution. The product iscollected by filtration and then dissolved in methylene chloride, themixture is filtered through diatomaceous earth, and brine is added tobreak the emulsion. The layers are separated, the organic phase is driedand evaporated. The residue is crystallized from toluene to yield theproduct as a white solid.

EXAMPLE 124N-{4-[15-(Trifluoromethyl)pentadecylamino]benzoyl}methanesulfonamide

A solution of 25.2 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoylchloride hydrochloride and 5.6 g. of methanesulfonamide in 250 ml. ofpyridine is stirred under reflux for 2 hours and then concentrated invacuo. The residue is partitioned between water and diethyl ether; theaqueous layer acidified with 1 N hydrochloric acid, and the organiclayer separated, dried over magnesium sulfate and evaporated.Crystallization of the residual white solid from 60% aqueous acetic acidand then from methylene chloride-hexane affords the product as a whitesolid.

EXAMPLE 125 N-{4-[15-(Trifluoromethyl)pentadecylamino]benzoyl}alanine

A solution of 4.75 g. of4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino]benzoylchloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treatedwith 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hotsolution is filtered, the residue is washed with hot ether, and thesolution is evaporated. After treatment with aqueous methanolicpotassium carbonate, the product is precipitated by acidification,filtered, and dried. Crystallization from acetone yields the product asa white, crystalline solid.

EXAMPLE 126 N-{4-[15-(Trifluoromethyl)pentadecylamino]-benzoyl}benzamide

One gram of a 50% oil dispersion of sodium hydride is washed withpetroleum ether by decantation, dried, and suspended in 5 ml. oftetrahydrofuran. To this stirred mixture is added a solution of 2.42 g.of benzamide in 5 ml. of tetrahydrofuran in one portion. An initialhydrogen evolution is observed. While stirring (30 minutes), the sodiumhydride gradually disappears and a white, milky, turbid mixture forms. Asolution of 0.9 g. of4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino]benzoylchloride in 3 ml. of tetrahydrofuran is added dropwise during 5 minutesto the mixture. The whole milky mixture is stirred at room temperatureunder nitrogen for one hour. The mixture is then poured into water andextracted with ether. The ether extract is washed with water and brineand dried over sodium sulfate. Evaporation of the solvent, affords apale yellow solid. The solid is recrystallized from ether/acetonitrile(50/50) and then from acetonitrile to yield the product as a whitesolid.

EXAMPLE 1271-{4-[15-(Trifluoromethyl)pentadecylamino]benzoyl}pyrrolidine

To a warm solution of4-[N-carbobenzoyloxy-15-(trifluoromethyl)pentadecylamino]benzoylchloride and 1.3 g. of triethylamine in 100 ml. ether is added 1.2 g. ofpyrrolidine. An immediate precipitate forms, the mixture is refluxed forone hour and then filtered. The solid is extracted several times withhot ether, and the ether is evaporated to yield a white solid. The solidis dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg.10% palladium-on-carbon at 50 psi. until hydrogen up-take stops. Thecatalyst is filtered and the filtrate evaporated. The residue iscrystallized from acetic acid to yield the product as a white solid.

EXAMPLE 128N-(2,3-Dihydroxypropyl)-4-[15-(trifluoromethyl)pentadecylamino]benzamide

To a mixture containing 4.3 g. of1-{4-[N-tert-butyloxycarbonyl)]-4-[15-(trifluoromethyl)pentadecylamino]benzoyl}imidazole,50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g.of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24hours, the layers are separated, and the chloroform solution is washedonce with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated andthe residue is heated for 30 minutes at 40° C. in 50 ml. of anhydroustrifluoroacetic acid. The solvent is again evaporated and the oil iscrystallized from acetone to yield the product as a light yellow solid.

TABLE IV

The following benzamides are prepared from the carboxylic acids of TableI (or activated derivatives thereof prepared by the methods of Examples73-76) by the methods of Examples 120-128 as shown in the table.

    ______________________________________                                        Example                                                                       No.    Method of Example                                                                           Compound                                                 ______________________________________                                        129    120           1-{4-[11-(Trifluoromethyl)-                                                   undecylamino]benzoyl}piperi-                                                  dine                                                     130    120           1-{3-[12-Fluoro-12-(hepta-                                                    fluoropropyl)-12-(trifluoro-                                                  methyl)dodecylamino]benzoyl}-                                                 pyrrolidine                                              131    120           1-{4-[5-(Pentadecafluorohep-                                                  tyl)-4-pentenylamino]benzoyl}-                                                piperidine                                               132    120           1-{4-[3-(2,2,2-Trifluoroeth-                                                  yl)-2,4,4-trimethylcyclo-                                                     pentylamino]benzoyl}pyrroli-                                                  dine                                                     133    121           Ethyl 4-[5-(pentadecafluoro-                                                  heptyl)pentylamino]hippurate                             134    121           Ethyl 4-[7-(trifluoromethyl)-                                                 heptylamino]hippurate                                    135    121           Ethyl 4-[ 1-hexyl-9-(trifluoro-                                               methyl)-4-nonynylamino]hip-                                                   purate                                                   136    121           Ethyl 4-[3-(trifluoromethyl)-                                                 2,4,4-trimethylcyclohexyl-                                                    amino]hippurate                                          137    122           N-{4-[ 5-(Pentadecafluorohep-                                                 tyl)pentylamino]benzoyl}gly-                                                  cine                                                     138    122           N-{4-[7-(Trifluoromethyl)-                                                    heptylamino]benzoyl}glycine                              139    122           N-{4-[1-Hexyl-9-(trifluoro-                                                   methyl)-4-nonynylamino]ben-                                                   zoyl}glycine                                             140    122           N-{4-[3-(Trifluoromethyl)-                                                    2,4,4-trimethylcyclohexyl-                                                    amino]benzoyl}glycine                                    141    123           4-[14,14-(Difluoro)penta-                                                     decylamino]-N-(phenylsulfo-                                                   nyl)benzamide                                            142    123           4-[15-Trifluoromethyl)-4-                                                     pentadecynylamino]-N-(phen-                                                   ylsulfonyl)benzamide                                     143    123           4-[18-(Trifluoromethyl)octa-                                                  decylamino]-N-(phenylsulfo-                                                   nyl)benzamide                                            144    123           4-[11-(Nonafluorobutyl)undecyl-                                               amino]-N-(phenylsulfonyl)-                                                    benzamide                                                145    124           N-{4-[11-(Undecafluoropentyl)-                                                undecylamino]benzoyl}methane-                                                 sulfonamide                                              146    124           N-{4-[11,11-Difluoro-16-(tri-                                                 fluoromethyl)hexadecylamino]-                                                 benzoyl}methanesulfonamide                               147    124           N-[4-(15,15-Difluorohexadecyl-                                                amino)benzoyl]methanesulfon-                                                  amide                                                    148    125           N-{4-[15-(Trifluoromethyl)-                                                   4-pentadecynylamino]benzoyl}-                                                 alanine                                                  149    125           N-{4-[7-(Trifluoromethyl)-                                                    heptylamino]benzoyl}alanine                              150    126           N-{4-[1-(2,2,2-Trifluoroeth-                                                  yl)pentadecylamino]benzoyl}-                                                  benzamide                                                151    126           N-[4-(11,11-Difluorododecyl-                                                  amino)benzoyl]benzamide                                  152    126           N-{4-[(Hentricontafluoropen-                                                  tadecyl)methylamino]benzoyl}-                                                 benzamide                                                153    127           1-{4-[16-(Pentafluoroethyl)-                                                  hexadecylamino]benzoyl}pyrrol-                                                idine                                                    154    127           1-{4-[ 3-(Trifluoromethyl)-                                                   2,4,4-trimethylcyclohexyl-                                                    amino]benzoyl}piperidine                                 155    128           N-(2,3-Dihydroxypropyl)-4-                                                    (16,16-difluoroheptadecyl-                                                    amino)benzamide                                          156    128           N-(2,3-Dihydroxypropyl)-4-                                                    [1-(2,2,2-trifluoroethyl)-                                                    pentadecylamino]benzamide                                ______________________________________                                    

EXAMPLE 157 Diethyl4-[15-(trifluoromethyl)pentadecylamino]benzoylmalonate

A solution of 26.6 g. of diethyl malonate and 10 ml. of1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydridein 1,2-dimethoxyethane under argon. A solution of 17.3 g. of4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in1,2-dimethoxyethane is then added. The reaction mixture is refluxed for4.5 hours, cooled, poured on ice, acidified, and extracted with ether.The ether solution is washed with water and saturated sodium chloridesolution, dried over anhydrous sodium sulfate and concentrated todryness. Addition of a small amount of ethanol to the residue gives asolid which is filtered and discarded. The ethanol filtrate isconcentrated and the residue is recrystallized from ether to yield theproduct.

EXAMPLE 158 tert-Butyl ethyl4-[15-(trifluoromethyl)pentadecylamino]benzoylmalonate

A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydridein 1,2-dimethoxyethane under argon. A solution of 17.3 g. of4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in1,2-dimethoxyethane is then added. The reaction mixture is refluxed for5 hours, cooled, poured on ice and extracted with ether. The ethersolution is washed with water and saturated sodium chloride solution,dried over anhydrous sodium sulfate and concentrated to dryness. Theresidue is then recrystallized from ether to yield the product.

EXAMPLE 159 Ethyl2-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}acetoacetate

A solution of 21.6 g. of ethyl acetoacetate and 10 ml. of1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydridein 1,2-dimethoxyethane under argon. A solution of 17.3 g. of4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in1,2-dimethoxyethane is then added. The reaction mixture is refluxed for5 hours, cooled, poured on ice and extracted with ether. The ethersolution is washed with water and saturated sodium chloride solution,dried over anhydrous sodium sulfate and concentrated to dryness.Recrystallization from ether affords the product as a white solid.

EXAMPLE 160 Ethyl 4-[15-(trifluoromethyl)pentadecylamino]benzoylacetate

A solution of 3.0 g. of tert-butyl ethyl4-[15-(trifluoromethyl)pentadecylamino]benzoylmalonate and 10 ml. oftrifluoroacetic acid is warmed with stirring for 3 hours. The solutionis poured onto ice and neutralized with potassium hydroxide. Theresulting precipitate is collected by filtration, washed with water anddried. Recrystallization from chloroform affords the product as a whitesolid.

EXAMPLE 161 4-[15-(Trifluoromethyl)pentadecylamino]benzoylacetic acid

Two grams of ethyl 4-[15-(trifluoromethyl)pentadecylamino]benzoylacetateis added to a solution of potassium hydroxide in 50 ml. of 1:9water-ethanol. The reaction mixture is stirred for 24 hours at roomtemperature. Careful neutralization with sulfuric acid gives aprecipitate which is filtered, washed with water, and dried to yield theproduct.

EXAMPLE 1624'-[15-(Trifluoromethyl)pentadecylamino]-2-(methylsulfinyl)acetophenone

To a solution of 5.8 g. of dimethyl sulfoxide, dried over sieves, and 50ml. of tetrahydrofuran is slowly added 28 ml. of n-butyl lithium (2.42 Min hexane). To this mixture is added 10 g. of methyl4-[15-(trifluoromethyl)pentadecylamino]benzoate in 200 ml. oftetrahydrofuran. After two hours, the reaction mixture is poured ontoice, acidified with dilute hydrochloric acid and quickly extracted withchloroform. The chloroform extract is washed with water and saturatedsodium chloride solution and dried over anhydrous sodium sulfate.Concentration affords a solid which is washed with hexane. The whitesolid is dried in vacuo to yield the product.

EXAMPLE 1634'-[15-(Trifluoromethyl)pentadecylamino]-2-(phenylsulfonyl)acetophenone

A solution of 864 mg. of sodium hydride and 5.3 g. ofmethylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60°C. for one hour under an atmosphere of argon. To this solution is thenadded a solution of 5.0 g. of methyl4-[15-(trifluoromethyl)pentadecylamino]benzoate and 50 ml. oftetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5hours. The mixture is cooled, poured onto ice, acidified with dilutehydrochloric acid to pH 3 and then extracted with chloroform. Theorganic layer is separated, washed three times with water and saturatedsodium chloride solution, dried over anhydrous sodium sulfate and thenconcentrated to dryness. The crude solid is chromatographed on silicagel, eluting with methylene chloride to yield the product.

EXAMPLE 1644'-[15-(Trifluoromethyl)pentadecylamino]-2-(phenylsulfinyl)acetophenone

To a solution of 6.2 g. of methylphenylsulfoxide, dried over sieves, and50 ml. of tetrahydrofuran is slowly added 28 ml. of n-butyl lithium(2.42 M in hexane). To this mixture is added 10 g. of methyl4-[15-(trifluoromethyl)pentadecylamino benzoate in 200 ml. oftetrahydrofuran. After two hours, the reaction mixture is poured intoice, acidified with diluted hydrochloric acid and quickly extracted withchloroform. The chloroform layer is washed with water and saturatedsodium chloride solution and dried over anhydrous sodium sulfate.Concentration affords a solid which is washed with 500 ml of hot hexane,filtered while hot, and then washed with 50 ml. of hexane. The whitesolid is dried in vacuo yielding the product.

EXAMPLE 1653-{4-[15-(Trifluoromethyl)pentadecylamino]benzoyl}-2,4-pentanedione

A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of1,2-dimethoxyethane is added to a suspension of 13.6 g. of sodiumhydride in 220 ml. of 1,2-dimethoxyethane under argon. A solution of28.7 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloridehydrochloride in 1,2-dimethoxyethane is then added. The reaction mixtureis stirred at room temperature for 12 hours, cooled, poured on ice-andextracted with ether. The ether solution is washed with water andsaturated sodium chloride solution, dried over anhydrous sodium sulfateand concentrated. The residue is then chromatographed over silica gel toyield the product as a white solid.

EXAMPLE 166 3-{4-[15-(Trifluoromethyl)pentadecylamino]benzoyl}propionicacid

A mixture of 35 g. of 3-(4-acetamidobenzoyl)propionic acid, 700 ml. ofmethanol and 1.4 ml. of concentrated sulfuric acid is refluxed for 76hours. The solution is cooled to 35° C. and poured onto 7 g. ofanhydrous sodium acetate while stirring. The reaction mixture is stirredin an ice-bath. The solid is collected and washed with cold methanol toyield methyl 3-(4-aminobenzoyl)propionate as a white solid. A mixture ofthis solid, 9.2 g. of 15-(trifluoromethyl)pentadecyl bromide and 4.2 g.of potassium carbonate is stirred for 20 hours at 125° C. undernitrogen. The mixture is then cooled to 25° C. and 30 ml. of water isadded. After stirring, the product is filtered and washed with water.Recrystallization from methanol affords methyl3-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}propionate as a whitesolid.

A solution of 5.4 g. of methyl3-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}propionate is stirredwith 5.4 g. of potassium hydroxide in 100 ml. of 95% ethanol for 3 hoursat reflux. The reaction mixture is cooled, diluted with 50 ml. ofethanol and 100 ml. of water, and neutralized with hydrochloric acid.The solution is cooled to room temperature and filtered. The white solidis washed with 50% aqueous ethanol and dried. The product isrecrystallized from ethanol to yield3-{4-[15-(trifluoromethyl)pentadecylamino]benzoyl}propionic acid as awhite crystalline solid.

TABLE V

The following benzamides are prepared from the benzoic acids andbenzoate esters of Tables I and II (or activated derivatives thereofprepared by the methods of Examples 73-76) by the methods of Examples157-166 as shown in the table.

    ______________________________________                                        Example                                                                       No.    Method of Example                                                                           Compound                                                 ______________________________________                                        167    157           Diethyl 4-[(hentricontafluoro-                                                pentadecyl)methylamino]ben-                                                   zoylmalonate                                             168    157           Diethyl 4-[15-(trifluoro-                                                     methyl)-12-pentadecenylamino]-                                                benzoylmalonate                                          169    158           tert-Butyl ethyl 4-(11,11-                                                    difluorododecylamino)benzoyl-                                                 malonate                                                 170    158           tert-butyl ethyl 4-[12-fluoro-                                                12-(heptafluoropropyl)-12-                                                    (trifluoromethyl)dodecyla-                                                    mino]benzoylmalonate                                     171    159           Ethyl 2-{4-[9-(trifluorometh-                                                 yl)nonylamino]benzoyl}aceto-                                                  acetate                                                  172    159           Ethyl 2-{4-[11,11-difluoro-                                                   16-(trifluoromethyl)hexadec-                                                  ylamino]benzoyl}acetoacetate                             173    160           Ethyl 4-(16,16-difluorohepta-                                                 decylamino)benzoylacetate                                174    160           Ethyl 4-[12-fluoro-12-(hepta-                                                 fluoropropyl)-12-(trifluoro-                                                  methyl)dodecylamino]benzoyl-                                                  acetate                                                  175    161           4-(16,16-Difluoroheptadecyl-                                                  amino)benzoylacetic acid                                 176    161           4-[ 12-Fluoro-12-(heptafluoro-                                                propyl)-12-(trifluoromethyl)-                                                 dodecylamino]benzoylacetic                                                    acid                                                     177    162           4'-[11-(Nonafluorobutyl)un-                                                   decylamino]-2-(methylsulfin-                                                  yl)acetophenone                                          178    162           4'-[ 12-(Trifluoromethyl)do-                                                  decylamino]-2-(methylsulfin-                                                  yl)acetophenone                                          179    162           4'-[3-(Trifluoromethyl)-2,4,4-                                                trimethylcyclohexylamino]-                                                    2-(methylsulfinyl)acetophe-                                                   none                                                     180    163           4'-(14,14-Difluoropentadecyl-                                                 amino)-2-(phenylsulfonyl)-                                                    acetophenone                                             181    163           4'-[1-(2,2,2-Trifluoroethyl)-                                                 decylamino]-2-(phenylsulfo-                                                   nyl)acetophenone                                         182    164           4'-[7-(Trifluoromethyl)un-                                                    decylamino]-2-(phenylsulfin-                                                  yl)acetophenone                                          183    164           4'-[1-Hexyl-11-(trifluoro-                                                    methyl)undecylamino]-2-(phen-                                                 ylsulfinyl)acetophenone                                  184    165           3-{4-[ 13-(Trifluoromethyl)-                                                  tridecylamino]benzoyl}2,4-                                                    pentanedione                                             185    165           3-[4-(15,15-Difluorohexadec-                                                  ylamino)benzoyl]-2,4-pentane-                                                 dione                                                    186    166           3-{4-[3-(2,2,2-Trifluoroeth-                                                  yl)-2,4,4-trimethylcyclopen-                                                  tylamino]benzoyl}propionic                                                    acid                                                     187    166           3-{4-[12-Fluoro-12-(hepta-                                                    fluoropropyl)-12-(trifluoro-                                                  methyl)dodecylamino]benzoyl}-                                                 propionic acid                                           ______________________________________                                    

EXAMPLE 188 4-[15-(Trifluoromethyl)pentadecylamino]phenylacetic acid

A solution of 8.2 g. of 4-aminophenylacetic acid, 150 ml. of absoluteethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for15 hours. The solution is concentrated by distillation and thenevaporated to dryness in vacuo. The residue is dissolved in ethyl ether,washed with aqueous sodium bicarbonate dried and evaporated to yieldethyl 4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of15-(trifluoromethyl)pentadecyl bromide, 4.2 g. of anhydrous potassiumcarbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for7 hours. The mixture is then cooled, diluted with water, and extractedwith ethyl ether. The ether extracts are washed with water, dried andevaporated. The residue is recrystallized from a mixture of chloroformand hexane, yielding ethyl4-[15-(trifluoromethyl)pentadecylamino]phenylacetate. A mixture of 6.0g. of this ester, 7.0 g. of potassium hydroxide and 100 ml. ofethanol-water is heated to reflux for 4 hours. While hot, the mixture isadjusted to pH 7 with concentrated hydrochloric acid. The mixture isdiluted with water, cooled and filtered. Recrystallization of theprecipitate yields the product as a white solid.

EXAMPLE 189 4-[15-(Trifluoromethyl)pentadecylamino]hydrocinnamic acid

A mixture of 5.0 g. of 4-nitrocinnamic acid and 100 mg. of 10%palladium-on-carbon in 200 ml. of ethanol containing 5 drops of 5.5 Nethanolic hydrogen chloride is treated with hydrogen in a Parr apparatusat room temperature for 3 hours. The mixture is then filtered throughcelite and the filtrate is concentrated, affording 4-aminohydrocinnamicacid.

A solution of 10.0 g. 4-aminohydrocinnamic acid in 100 ml. of absoluteethanol containing 16 ml. of boron trifluoride etherate is heated toreflux for 48 hours. The solution is then cooled, poured into 5% aqueoussodium carbonate, and extracted with methylene chloride. Evaporation ofthe organic extracts yields ethyl 4-aminohydrocinnamate.

In a manner directly analogous to that described in Example 8, ethyl4-aminohydrocinnamate is alkylated with 15-(trifluoromethyl)pentadecylbromide to form ethyl4-[15-(trifluoromethyl)pentadecylamino]hydrocinnamate. Subsequently, ina manner directly analogous to that described in Example 9, ethyl4-[15-(trifluoromethyl)pentadecylamino]hydrocinnamate is hydrolyzed to4-[15-(trifluoromethyl)pentadecylamino]hydrocinnamic acid.

EXAMPLE 190 4-[15-(Trifluoromethyl)pentadecylamino]cinnamic acid

A mixture of ethyl 4-aminocinnamate, one equivalent of15-(trifluoromethyl)pentadecyl bromide and one equivalent of anhydrouspotassium carbonate in hexamethylphosphoramide is heated for 20 hours at60° C. The mixture is then cooled, diluted with water and extracted withether. The combined ether extracts are dried, filtered and evaporated toprovide ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate. Theester is hydrolyzed with sodium hydroxide in a 1:9 water:ethanolsolution at steam bath temperatures for 10 hours. The hot solution isthen acidified with acetic acid, cooled and filtered and the solid iswashed with water. Recrystallization from chloroform yields the productas a white solid.

EXAMPLE 191 4-[15-(Trifluoromethyl)pentadecylamino]phenylpropiolic acid

A sample of 50 g. of ethyl 4-aminocinnamate is dissolved in 500 ml. ofethyl ether and a solution of 28 g. of trifluoroacetic anhydride in 30ml. of ether is added dropwise. When the addition is complete, thereaction is allowed to stir for another hour. The mixture is thendiluted with hexane and filtered, providing ethyl4-trifluoroacetamidocinnamate.

A solution of 40 g. of ethyl 4-trifluoroacetamido cinnamate in 200 ml.of carbon tetrachloride is cooled in ice. Bromine (28 g.) is addeddropwise, the reaction is allowed to stir for one additional hour andthen the solvent is evaporated. The crystalline residue is the dibromoester.

A solution of 11.4 g. of potassium hydroxide in 300 ml. of 95% ethanolis cooled to 40° C. and 20 g. of the crude dibromo ester above is added.After 30 minutes, the reaction is heated to reflux for five hours. Thesolution is then cooled and filtered. The filtrate is treated withacetic acid until the solution is neutral to litmus, then concentrated,chilled and filtered, to yield 4-aminophenylpropiolic acid.

The 4-aminophenylpropiolic acid is converted to4-[15-(trifluoromethyl)pentadecylamino]phenylpropiolic acid in themanner of Example 188.

TABLE VI

The following carboxylic acids are prepared by alkylation of thecorresponding 4-aminophenyl carboxylate ester with the appropriatepolyfluoroalkyl halide, trifluoromethanesulfonate, or methanesulfonatefollowed by hydrolysis using the methods of Examples 188-191 as shown inthe table.

    ______________________________________                                        Example                                                                       No.    Method of Example                                                                           Compound                                                 ______________________________________                                        192    188           4-[7-(Trifluoromethyl)heptyl-                                                 amino]phenylacetic acid                                  193    188           4-[16-(Trifluoromethyl)hexa-                                                  decylamino]phenylacetic acid                             194    188           4-[1-Hexyl-11-(trifluoro-                                                     methyl)octylamino]phenyl-                                                     acetic acid                                              195    188           4-(3,3-Difluorotetradecyl-                                                    amino)phenylacetic acid                                  196    189           4-[(Hentricontafluoropenta-                                                   decyl)methylamino]hydrocin-                                                   namic acid                                               197    189           4-[15-(Trifluoromethyl)-4-                                                    pentadecynylamino]hydro-                                                      cinnamic acid                                            198    189           4-[11-(Trifluoromethyl)un-                                                    decylamino]hydrocinnamic acid                            199    189           4-[1-(2,2,2-Trifluoroethyl)-                                                  tridecylamino]hydrocinnamic                                                   acid                                                     200    190           4-[11-(Heptafluoropropyl)-                                                    undecylamino]cinnamic acid                               201    190           4-[ 12-Fluoro-12-(heptafluoro-                                                propyl)-12-(trifluoromethyl)-                                                 dodecylamino]cinnamic acid                               202    190           4-[15-(Trifluoromethyl)-9-                                                    pentadecenylamino]cinnamic                                                    acid                                                     203    190           4-[1-Hexyl-9-(trifluorometh-                                                  yl)-4-nonynylamino]cinnamic                                                   acid                                                     204    191           4-[14-(Trifluoromethyl)tetra-                                                 decylamino]phenylpropiolic                                                    acid                                                     205    191           4-[3,7-Dimethyl-7-(trifluoro-                                                 methyl)octylamino]phenylpro-                                                  piolic acid                                              206    191           4-(11,11-Difluorododecyla-                                                    mino)phenylpropiolic acid                                207    191           4-[3-(Trifluoromethyl)-2,4,4-                                                 trimethylcyclohexylamino]-                                                    phenylpropiolic acid                                     ______________________________________                                    

I claim:
 1. A compound of the formula ##STR3## wherein R₁ is a saturatedor unsaturated hydrocarbon radical of 7-19 carbon atoms which may bebranched or unbranched and which may contain a saturated or unsaturatedcycloalkyl group, said radical containing one or more perfluorinated(--CF₂ -- or --CF₃) carbon atoms excluding the carbon adjacent to thenitrogen atom; R₂ is selected from the group consisting of hydrogen,methyl, carboxymethyl, acetyl, succinyl, 1-(sodiumsulfo)loweralkyl,1-(sodiumsulfo)polyhydroxyalkyl, and 3-aryl-1,3-bis(sodiumsulfo)alkyl;and J is carboxyloweralkyl, carboxyloweralkenyl, carboxyloweralkynyl,carboalkoxyloweralkyl, carboalkoxyloweralkenyl, carboalkoxyloweralkynyl;and the pharmaceutically acceptable non-toxic acid-addition and cationicsalts thereof.
 2. A compound of the formula ##STR4## wherein R₁ is asaturated or unsaturated hydrocarbon radical of 7-19 carbon atoms whichmay be branched or unbranched and which may contain a saturated orunsaturated cycloalkyl group, said radical containing one or moreperfluorinated (--CF₂ -- or --CF₃) carbon atoms excluding the carbonadjacent to the nitrogen atom; and J is carboxyloweralkyl,carboxyloweralkenyl, carboxyloweralkynyl, carboalkoxyloweralkyl,carboalkoxyloweralkenyl, carboalkoxyloweralkynyl; and thepharmaceutically acceptable non-toxic acid-addition and cationic saltsthereof.
 3. The compound of4-[15-(trifluoromethyl)pentadecylamino]phenylacetic acid.
 4. Thecompound 4-[15-(trifluoromethyl)pentadecylamino]hydrocinnamic acid. 5.The method of inhibiting atherosclerotic lesion development in mammalcomprising the administration of an effective lesion-developmentinhibiting amount of a compound of claim 1 to said mammal.
 6. The methodof claim 5, wherein said compound is administered to provide a dailydosage of from about one mg. to about 250 mg. per kilogram of bodyweight of said mammal.
 7. An antiatherosclerotic composition indosage-unit form useful for preventing or diminishing atheroscleroticlesion formation in mammals comprising from about one mg. to about 250mg. per kilogram of body weight per daily dosage unit of a compound ofclaim
 1. 8. The method of inducing regression of atherosclerotic lesiondevelopment in a mammal comprising administering to said mammal aneffective lesion-regressive amount of a compound of claim
 1. 9. Themethod of claim 8, wherein said compound is administered to provide adaily dosage of from about one mg. to about 250 mg. per kilogram of bodyweight of said mammal.
 10. The method of treating hyperlipidemia andhyperlipoproteinemia and/or altering the lipoprotein pattern in a mammalcomprising administering to said mammal an effective lipid-alteringamount of a compound of claim 1.